This invention relates to novel diphenyl ether compounds which inhibit monoamine re-uptake. In particular compounds of the present invention exhibit activity as selective serotonin re-uptake inhibitors (SSRIs) and have utility therefore in a variety of therapeutic areas. Notably the compounds of the present invention are useful in the treatment or prevention of a variety of disorders, including those in which the regulation of monoamine transporter function is implicated, such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including premature ejaculation, and to pharmaceutical formulations containing such compounds.
According to a first aspect, the invention provides a compound of general formula (I), pharmaceutically acceptable salts, solvates or polymorphs thereof; 
wherein:
R1 is H or C1-C6 alkyl;
R2 and R3, together with the interconnecting atoms form a 4 to 8-membered saturated ring containing one or two heteroatoms (includingthe nitrogen to which R2 is attached) wherein a second heteroatom, if present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent heteroatoms;
Z is CF3, OCF3, C1-C6alkylthio or C1-C6alkoxy;
Y is hydrogen, halogen, xe2x80x94ORa, Ra or C1-C6alkylthio, and wherein Ra is C1-C4 alkyl optionally substituted with fluorine atoms;
or when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
R4 and R5, which may be the same or different, are:
Axe2x80x94X, wherein A=xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)pxe2x80x94 where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR6R7, SO2NR6R7, SO2NHC(xe2x95x90O)R6, OH, C1-4alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10; R6, R7, R8 and R10 which may be the same or different, are hydrogen or C1-6alkyl optionally substituted independently by one or more R12; R9 is C1-6 alkyl optionally substituted independently by one or more R12; R11 is hydrogen, C1-6 alkyl optionally substituted independently by one or more R12, C(O)R6, CO2R9, C(O)NHR6 or SO2NR6R7; R12 is F (preferably up to 3), OH, CO2H, C3-6cycloalkyl, NH2, CONH2, C1-6alkoxy, C1-6alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O optionally substituted independently by one or more R13; or R6 and R7, together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered heterocyclic ring optionally substituted independently by one or more R13; or
a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally substituted independently by one or more R13; wherein R13 is hydroxy, C1-C4alkoxy, F, C1-C6alkyl, haloalkyl, haloalkoxy, xe2x80x94NH2, xe2x80x94NH(C1-C6alkyl) or xe2x80x94N(C1-C6alkyl)2.
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term heterocyclic should be similarly construed.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The term carbocylic should be similarly construed. In addition, the term carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
Halo means fluoro, chloro, bromo or iodo.
Preferably R1 is hydrogen or methyl (more preferably hydrogen).
Preferably R2 and R3, together with the interconnecting atoms, form a pyrrolidine ring.
Preferably at least one of Z or Y is para to the ether linkage linking ring A and ring B and is not hydrogen. More preferably the other Z or Y is meta to the ether linkage linking ring A and ring B.
Preferably Z is CF3, OCF3, SMe, SEt or OMe;
Y is hydrogen, F, Cl, Br, methyl, ethyl, OMe, SMe or SEt; or when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 or 6-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen (preferred linkages forming the fused ring are xe2x80x94(CH2)3xe2x80x94, xe2x80x94S(CH2)2xe2x80x94, xe2x80x94CH2Sxe2x80x94CH2xe2x80x94, xe2x80x94SCHxe2x95x90Nxe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94S(CH2)2Oxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x95x90CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90Nxe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, wherein either end of these linkages can be attached para to the ether linkage).
Preferably R4 and R5 are not both hydrogen.
Preferably R4 and R5, which may be the same or different, are:
xe2x80x94(CH2)pxe2x80x94X, where p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 wherein R6, R7, R8, R9 and R10 are as defined in the first aspect; or
a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O (preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl).
More preferably R4 and R5,which may be the same or different, are:
xe2x80x94(CH2)pxe2x80x94X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R6 and R7, which may be the same or different, are hydrogen or C1-C3alkyl optionally substituted by hydroxy, xe2x80x94CONH2 or C1-C3alkoxy (preferably methoxy); R8 is hydrogen, hydroxyethyl or methyl; or R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still R4 is hydrogen.
Preferably R6 and R7, which may be the same or different, are hydrogen, C1-C3alkyl optionally substituted by hydroxy, xe2x80x94CONH2 or C1-C3alkoxy (preferably methoxy). More preferably R6 and R7, which may be the same or different, are hydrogen or methyl, more preferably still hydrogen.
When present, R12 is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.
Preferably R11 is hydrogen or C1-6 alkyl.
Preferably R8 is hydrogen, hydroxyethyl or methyl. More preferably hydrogen.
Preferably R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. More preferably methyl or ethyl (preferably methyl).
Preferably R10 is methyl or ethyl.
Preferably p is 1 or 0, more preferably 0.
Preferably
R1 is hydrogen or methyl;
R2 and R3, together with the interconnecting atoms form a 4 to 8-membered saturated ring containing one or two heteroatoms (including the nitrogen to which R2 is attached) wherein a second heteroatom, if present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent heteroatoms;
at least one of Z or Y is para to the ether linkage linking rings A and B and is not hydrogen; when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and
R4 and R5, which may be the same or different, are
(CH2)pxe2x80x94X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 and wherein R6 and R7, which may be the same or different, are hydrogen, C1-C3alkyl optionally substituted by hydroxy, xe2x80x94CONH2 or C1-C3alkoxy (preferably methoxy); or R6 and R7, together with the nitrogen to which they are attached, may form a morpholine, pyrrolidine or piperidine ring each of which may be substituted by OH or CONH2; R8 is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; and R10 is methyl or ethyl; or
an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl group.
More preferably
R1 is hydrogen or methyl;
R2 and R3, together with the interconnecting atoms, form a pyrrolidine ring;
Z is CF3, OCF3, SMe, SEt or OMe;
Y is hydrogen, F, Cl, Br, methyl, ethyl, OMe, SMe or SEt; wherein at least one of Z or Y is para to the ether linkage linking ring A and ring B and is not hydrogen and the other Z or Y is meta to the ether linkage linking ring A and ring B; or when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 or 6-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and
R4 and R5, which may be the same or different, are
xe2x80x94(CH2)pxe2x80x94X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R6 and R7, which may be the same or different, are hydrogen, C1-C3alkyl optionally substituted by hydroxy, xe2x80x94CONH2 or C1-C3alkoxy (preferably methoxy); R8 is hydrogen, hydroxyethyl or methyl; R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still
R1 is hydrogen;
R2 and R3, together with the interconnecting atoms, form a pyrrolidine ring;
Z is CF3, OCF3, SMe, or OMe;
Y is hydrogen, F, Cl, Br, methyl, ethyl, OMe or SMe; wherein at least one of Z or
Y is para to the ether linkage linking ring A and ring B and is not hydrogen and the other Z or Y is meta to the ether linkage linking ring A and ring B; or
when Z and Y are attached para and meta to the ether linkage linking rings A and B, Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 or 6-membered carbocyclic or heterocyclic ring wherein the linkages forming the fused ring are xe2x80x94(CH2)3xe2x80x94, xe2x80x94S(CH2)2xe2x80x94, xe2x80x94CH2Sxe2x80x94CH2xe2x80x94, xe2x80x94SCHxe2x95x90Nxe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94S(CH2)2Oxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x95x90CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90Nxe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, wherein either end of these linkages can be attached para to the ether linkage;
R4 is hydrogen, and
R5 is xe2x80x94(CH2)pxe2x80x94X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R6 and R7, which may be the same or different, are hydrogen, C1-C3alkyl optionally substituted by hydroxy, xe2x80x94CONH2 or C1-C3alkoxy (preferably methoxy); R8 is hydrogen, hydroxyethyl or methyl; R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or
triazolyl, imidazolyl or pyrazolyl.
More preferably still R4 and R5 are not both hydrogen.
Preferred compounds of formula (I) are:
(+) 4-[4-(methylsulfanyl)phenoxy]-3-(2-pyrrolidinyl)benzenesulfonamide hydrochloride;
N-methyl-4-[4-(methylsulfanyl)phenoxy]-3-(2-pyrrolidinyl)benzenesulfonamide;
N-methyl-N-{3-(2-pyrrolidinyl)-4-[4-(trifluoromethoxy)phenoxy]phenyl}-methanesulfonamide; and
(+) N-{3-(2-pyrrolidinyl)-4-[4-(trifluoromethoxy)phenoxy]phenyl}-methanesulfonamide.
According to a second aspect, the invention provides a compound of general formula (I) or (IX): 
and pharmaceutically acceptable salts or solvates thereof wherein:
R1 represents H or C1-C6 alkyl,
R2 and R3, together with the nitrogen to which R2 is attached and the carbon to which R3 is attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R2 is attached, wherein a second heteroatom, if present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent heteroatoms;
Z is selected from the group including: CF3, OCF3, SR12 or C1-C4 alkoxy and
wherein R12 represents C1-C6 alkyl; and
Y is selected from the group including: hydrogen, halogen, xe2x80x94ORa, Ra or xe2x80x94SR12, and wherein Ra represents: C1-C4 alkyl (optionally substituted with fluorine atoms e.g. xe2x80x94CF3);
or Z and Y when taken together can represent a fused 5 to 7 membered ring as illustrated by general formula IX, wherein said 5 to 7 membered ring may be saturated, unsaturated or aromatic, and wherein said 5 to 7 membered ring may optionally contain one or more heteroatoms P and Q, wherein P and Q=may be independently O, S or N, and wherein E, F, or G independently represent CH or CH2 and wherein k and p may independently be=0, 1, 2 or 3, and m=1,2 or 3; and 
R4 and R5 independently represent Axe2x80x94X wherein Axe2x95x90xe2x80x94(CH2)nxe2x80x94, wherein n represents 0, 1 or 2 and wherein X represents: H, F, Cl, Br, I, CONR6R7 or SO2NR6R7, OH, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, S(O)mR10 wherein m=0, 1 or 2 and wherein R6, R7, R8 and R10 independently represent H or C1-6 alkyl, wherein R9 represents C1-6 alkyl, R11 represents H, C1-6 alkyl, C(O)R6, CO2R9; C(O)NHR6 or SO2NR6R6 and wherein said C1-6 alkyl group is optionally substituted by one or more groups selected from OH, CO2H, C3-6 cycloalkyl, NH2, CONH2, C1-6 alkoxy, C1-6 alkoxycarbonyl and a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; or
with the proviso that Z and Y together do not form a fused phenyl ring;
R4 or R5 may be representative of a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; and in addition, R6 and R7 may, together with the N atom to which they are attached, represent a 5- or 6-membered heterocyclic ring which may be optionally substituted; and pharmaceutically acceptable salts or solvates thereof with the proviso that both R4 and R5 are not H.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
The compounds of the invention have the advantage that they are selective inhibitors of the re-uptake of serotonin (SRIs) (and so are likely to have reduced side effects), they have a rapid onset of action (making them suitable for administration shortly before an effect is required), they have desirable potency and associated properties. Compounds that selectively inhibit the re-uptake of serotonin, but not noradrenaline or dopamine, are preferred.
We have found that compounds of formula I which possess these properties have a relatively polar group at R4/R5.
According to a third aspect, the invention provides a compound of general formula I and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, Z and Y are as defined in the first aspect; and R4 and R5, which may be the same or different, are xe2x80x94(CH2)pxe2x80x94Axe2x80x2, wherein p is 0, 1 or 2 and Axe2x80x2 is a polar group. In this aspect, polar groups may be defined as those having a negative xcfx80-value according to the formula:
xcfx80X=logPXxe2x88x92logPH 
wherein log PX is the partition coefficient of a derivative and PH is that of the parent compound as further described in C. Hansch and A. Leo, xe2x80x98Substitutent Constants for Correlation Analysis in Chemistry and Biologyxe2x80x99, Wiley, N.Y., 1979. In this system, H has a xcfx80-value of 0.00, xe2x80x94OCH3 has a xcfx80-value of xe2x88x920.02, and xe2x80x94SO2NH2 has a xcfx80-value of xe2x88x921.82, for example [see Table VI-I, xe2x80x98Well-Characterized Aromatic Substituentsxe2x80x99, p 49, ibid]. More preferred polar groups have a more negative xcfx80-value: thus, preferred groups have xcfx80-values of a greater negative value than xe2x88x920.1, more preferably a greater negative value than xe2x88x920.5, and most preferably a greater negative value than xe2x88x921.0. Even when p is other than zero in the above definition, the definition of Axe2x80x2 is based on the above reference as if p was zero.
The pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the HCl, HBr, Hl, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine and diethanolamine salts. For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19,1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.
The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
Also included within the scope of the compound and various salts of the invention are polymorphs thereof.
Hereinafter, compounds their pharmaceutically acceptable salts, their solvates or polymorphs, defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as xe2x80x9ccompounds of the inventionxe2x80x9d.
The compounds of the invention may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, xcex1-pyridonyl.
The invention also includes radiolabelled compounds.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of the invention, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of the invention may act as prodrugs of other compounds of the invention.
All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in xe2x80x9cDesign of Prodrugsxe2x80x9d by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference).
It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described by H. Bundgaard in xe2x80x9cDesign of Prodrugsxe2x80x9d (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
Preferred prodrugs for compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
Compounds of the invention may be prepared, in known manner in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated, R1 to R13, Z and Y are as defined in the first aspect. These processes form further aspects of the invention.
Throughout the specification, general formulae are designated by Roman numerals I, II, III, IV etc. Subsets of these general formulae are defined as Ia, Ib, Ic etc, . . . IVa, IVb, IVc etc.
Compounds of formula (Ia), i.e. compounds of general formula I where R2 and R3 form a pyrrolidine ring, may be prepared from compounds of formula (II) by reaction with a hydride reducing agent in a suitable solvent (see Scheme 1). Suitable solvents include protic solvents such as ethanol. Sodium borohydride is an appropriate reducing agent as exemplified by Example 1 herein. 
Compounds of general formula (II) may be prepared from compounds of formula (III) by treatment with acid in a suitable solvent under appropriate reaction conditions (see Scheme 2). Suitable solvents include 1,4-dioxane and suitable conditions are at elevated temperature as exemplified by Preparation 29 herein. 
Compounds of general formula (III) may be prepared from compounds of formula (IV) by reaction with the anion of 1-vinyl-2-pyrrolidinone (formed by treatment with an appropriate base) under suitable reaction conditions (see Scheme 3). Lithium hexamethyldisilazide is a suitable base and suitable conditions are under an inert atmosphere at reduced temperature, preferably below xe2x88x9220xc2x0 C. as exemplified by preparation 23 herein. 
Compounds of general formula (IV) may be prepared from compounds of formula (V), where T is a group which can be converted to the group xe2x80x94CO2R. 
i) When T is a halogen such as chloro, bromo or iodo, it may be converted to xe2x80x94CO2R by treatment with carbon monoxide at high pressure with a Pd(0) or (II) catalyst, in an alcohol solvent (ROH wherein R is C1-C4 alkyl), in the presence of a base at elevated temperatures. For example the reaction may be carried out at pressures in the region of about 60 p.s.i, whilst suitable Pd catalysts include palladium tetrakis(triphenylphosphine), suitable bases include triethylamine and suitable alcohol solvents include ethanol as exemplified by Preparation 21 herein.
ii) When T is a nitrile xe2x80x94CN, it may be converted to xe2x80x94CO2R by treatment with an acid in an alcohol solvent (ROH wherein R is C1-C4 alkyl) at elevated temperature. Alternatively a nitrile may be converted to xe2x80x94CO2R in two steps by first treating with a suitable hydroxide salt in the presence of water and a suitable co-solvent at elevated temperature to form compounds where T is xe2x80x94CO2H. Suitable hydroxide salts include sodium hydroxide and suitable co-solvents include ethanol, as exemplified by Preparation 7 herein. The group xe2x80x94CO2H may be converted to xe2x80x94CO2R by treatment with an acid in an alcohol solvent (ROH wherein R is C1-C4 alkyl) at elevated temperature. Suitable acids include concentrated sulfuric acid and appropriate alcohol solvents include ethanol as exemplified by Preparation 11 herein.
Compounds of formula (V) may be prepared in turn from the coupling of compounds of general formula (VI) with compounds of general formula (VII), wherein L is a suitable leaving group such as halogen (F, Cl, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, preferably L is F or Cl (see Scheme 5). Such coupling reaction may be accomplished by techniques known in the art, such as via reaction with potassium carbonate in a suitable solvent such as dimethylformamide under appropriate reaction conditions such as elevated temperature and in an inert atmosphere. 
Alternatively, R4 and/or R5 may be introduced after formation of the amine containing ring (see Scheme 6). Compounds of general formula (Ib) may be prepared from compounds of general formula (Ic), i.e. compounds of general formula (Ib) where R4 and R5 are hydrogen. Compounds of general formula (Ic) may be prepared from (IVa) in an analogous fashion to the preparation of (Ia) from (IV) (see Scheme 1), while compounds of general formula (IVa) may be prepared from (VII) and (VIa) in an analogous fashion to the preparation of (IV) (see Scheme 1). 
Methodologies for introducing R4 and/or R5 into compounds of formula (Ic) include:
i) Where R4/R5 are halogen, by reaction of (Ic) with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction. Suitable halogenating agents include trifluoromethanesulfonic acid and N-iodosuccinimide and suitable inert solvents include dichloromethane.
ii) Where R4/R5 are xe2x80x94NO2, by reaction of (Ic) with a suitable nitrating agent, such as an alkali metal nitrate, in an inert solvent which does not adversely affect the reaction at, or below, room temperature. Suitable nitrating agents include trifluoromethanesulfonic acid/potassium nitrate and suitable inert solvents include trifluoroacetic acid as exemplified by Example 16 herein.
iii) Where R4/R5 is xe2x80x94SO2NR6R7 by reaction of an intermediate sulfonyl chloride with the requisite amine of formula HNR6R7 in a suitable solvent. Suitable solvents include water and the reactions are generally performed at or below room temperature. The intermediate sulfonyl chlorides may be prepared from the amines (Ic) by reaction with chlorosulfonic acid under low temperature conditions and in the presence of an inert solvent which does not adversely affect the reaction. Suitable inert solvents include dichloromethane and a typical reaction temperature is 0xc2x0 C., as illustrated by Examples 6 and 7 herein.
Alternatively, compounds of general formula (I) having a particular R4/R5 substituent may be converted into other compounds of formula (I) using known techniques. For example:
i) When R4/R5 is nitro, it may be reduced to the corresponding xe2x80x94NH2 group via treatment with a reducing agent in a protic solvent at, or above, room temperature. Suitable reducing agents include iron powder/calcium chloride, suitable protic solvents include aqueous ethanol and at a typical reaction temperature of from about 70xc2x0 C. to about 100xc2x0 C., preferably about 90xc2x0 C., as exemplified by Preparation 15 herein.
ii) When R4/R5 is xe2x80x94NH2, it may be converted to the corresponding xe2x80x94NHSO2R9 group by reaction with a sulfonylating agent in the presence of a base in an inert solvent which does not adversely affect the reaction at, or below, room temperature. Suitable sulfonylating agents include methanesulfonyl chloride, suitable bases include triethylamine and suitable inert solvents include dichloromethane as exemplified by Preparations 40 and 41 herein.
iii) When R4/R5 is a xe2x80x94NHSO2R9 group, it may be converted to the corresponding xe2x80x94NR8SO2R group via treatment with an alkylating agent and a base in a suitable inert solvent. Examples of suitable alkylating agents include methyl iodide, suitable bases include potassium carbonate and suitable inert solvents include acetonitrile, as exemplified by Preparation 43 herein.
Compounds of general formula (I) having a particular R1 group may be converted into other compounds of formula (I) having a different R1 group.
For example, compounds of formula (I) wherein R1 is hydrogen, can be converted into compounds of formula (I) wherein R1 is alkyl, by reaction with an aldehyde and a hydride reducing agent. For example, compounds wherein R1 is methyl may be prepared in one step wherein the aldehyde is formaldehyde and suitable reducing agents include sodium triacetoxyborohydride. The reaction is preferably conducted in a solvent which does not interfere with the reaction, such as dichloromethane at or below room temperature, as exemplified by Example 12 herein. Alternatively the reaction may be conducted in two steps by reaction with a formylating agent in a suitable solvent, followed by subsequent reduction of the intermediate N-formyl compound with a hydride reducing agent in an inert solvent, preferably at elevated temperature. Suitable formylating agents include pentafluorophenyl formate (formed from formic acid, pentafluorophenol and dicyclohexylcarbodiimide) and suitable solvents for the formylation include dichloromethane as exemplified by Preparation 44 herein. Suitable reducing agents include borane-tetrahydrofuran complex and suitable inert solvents for the reduction include tetrahydrofuran as exemplified by Example 13 herein.
Compounds of general formula (VI) may be prepared in turn from compounds of general formula (VIII) (see Scheme 7). Compounds of formula (VI) may be prepared by aromatic electrophilic substitution of compounds of formula (VIII) to give compounds of formula (VI) directly. Alternatively compounds of formula (VI) may be prepared in two or more steps; aromatic electrophilic substitution of compounds of formula (VIII) to give intermediate compounds which then undergo further reaction to give compounds of formula (VI). The intermediate compounds may be isolated or generated in situ without isolation. 
According to further aspects, the invention provides compounds of formulae II, III, IV and V as defined above.
Compounds of formulae VI, VII and VIII are either known and available from commercial sources or are available from commercially available materials using known techniques (see Examples hereinafter).
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of formula I. This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 3rd edition, by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1999. Example 18 provides one example of a protecting group strategy employed in the synthesis of a compound of the present invention.
The skilled chemist will appreciate that diaryl ethers may be prepared using a number of synthetic methodologies. For a review of methodologies see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065, incorporated herein by reference.
The compounds of the invention are useful because they have pharmacological activity in mammals, including humans. More particularly, they are useful in the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated. Disease states that may be mentioned include hypertension, depression (e.g. depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression and grumpy old man syndrome), generalized anxiety disorder, phobias (e.g. agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g. anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g. addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g. dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g. dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g. hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying, sleeping disorder (cataplexy) and shock.
Disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including (in particular) premature ejaculation. Premature ejaculation may be defined as persistent or recurrent ejaculation before, upon or shortly after penile penetration of a sexual partner. It may also be defined as ejaculation occurring before the individual wishes [see xe2x80x98The Merck Manualxe2x80x99, 16th edition, p 1576, published by Merck Research Laboratories, 1992].
Thus, according to further aspects, the invention provides:
i) a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical;
ii) the use of a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated, for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation;
iii) the use of a compound of general formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of premature ejaculation, and also provides a method of treatment or prevention of premature ejaculation comprising the administration of this compound to a patient in need of such treatment or prevention;
iv) a method of treatment or prevention of depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation, which comprises administering a therapeutically effective amount of a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment or prevention;
v) a method of increasing ejaculatory latency which comprises the administration of an effective amount of a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, to a male desiring increased ejaculatory latency; and
vi) a compound of formula (I), as defined in the first aspect, or pharmaceutically acceptable salts, solvates or polymorphs thereof, for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated, for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
The compounds of the invention may be administered alone or as part of a combination therapy. If a combination of active agents are administered, then they may be administered simultaneously, separately or sequentially. In particular, the compounds of the invention may be combined with the following, preferably for the treatment of PE:
Alpha-blockers (e.g. phentolamine, doxazasim, tansulosin, terazasin, prazasin and Example 19 of WO9830560;
Apomorphinexe2x80x94teachings on the use of apomorphine as a pharmaceutical may be found in U.S. Pat. No. 5,945,117;
Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn compound number PNU95666);
Melanocortin receptor agonists (e.g. Melanotan II);
PGE1 receptor agonists (e.g. alprostadil);
Mono amine transport inhibitors, particularly Noradrenaline Re-uptake Inhibitors (NRIs) (e.g. Reboxetine), other Serotonin Re-uptake Inhibitors (SRIs) (e.g. paroxetine) or Dopamine Re-uptake Inhibitors (DRIs);
5-HT3 antagonists (e.g. ondansetron and granisetron); and
PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of EP 0771799-incorporated herein by reference) and in particular a PDE5 inhibitor (e.g. sildenafil, 1-{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine i.e. vardenafil/Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly)). 
For human use the compounds of the invention can be administered alone but in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention, can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications. The compounds of the invention may also be administered via intracavernosal injection. The compounds of the invention may also be administered via fast dispersing or fast dissolving dosage forms.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules, Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention, and their pharmaceutically acceptable salts, may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
The compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
Thus, for example, tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including PE), compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01 mg and 500 mg of a compound according to the present invention (or a salt thereof) whilst tablet fill weights may range from 50 mg to 1000 mg. An example formulation for a 10 mg tablet is illustrated:
The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 50 mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
The compounds of the invention may also be formulated for delivery via an atomiser. Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyidodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
For oral or parenteral administration to human patients the daily dosage levels of compounds of formula (I), and their pharmaceutically acceptable salts, will be from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range 0.01 to 5 mg/kg. Thus tablets will contain 1 mg to 0.4 g of compound for administration singly or two or more at a time, as appropriate. The physician will in any event determine the actual dosage which will be most suitable for any particular patient and it will vary with the age, weight and response of the particular patient. The above dosages are, of course only exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of the invention.
Oral administration is preferred. Preferably, administration takes place shortly before an effect is required.
For veterinary use, a compound of the invention, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or pro-drug thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus according to a further aspect, the invention provides a pharmaceutical formulation containing a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention is illustrated by the following non-limiting Examples in which the following abbreviations and definitions are used:
Where indicated, compounds were characterised as their hydrochloride salts. A typical procedure for formation of hydrochloride salts is given in Example 1. The procedure can be carried out with other solvents e.g. diethyl ether, EtOAc or DCM.